d-Limonene, the major terpenoid present in citrus oil, is presently undergoing phase I clinical evaluation as an antineoplastic agent in Great Britain. However, Dr. Michael Gould of the University of Wisconsin has demonstrated that perillyl alcohol (NSC 641066), a hydroxylated analog of d-limonene, was 5-10 times more potent in the regression of chemically induced rat mammary tumors. On the basis of these findings, perillyl alcohol recently received approval by the Decision Network Committee for Stage IIA preclinical development as an antitumor agent. Subsequently, in a cooperative effort with the Toxicology Branch (DTP, DCT, NCI), plasma specimens acquired from dogs and rats following oral treatment with perillyl alcohol during the dose-range finding component of its toxicological evaluation were analyzed for the administered compound and its major circulating metabolites, as reported by Dr. Gould. The only drug related peaks observed in chromatograms of plasma specimens acquired from male and female beagle dogs treated by gastric intubation (ig) with perillyl alcohol were the metabolites perillic acid and dihydroperillic acid. Plasma levels of perillic acid increased rapidly and decayed with an apparent biological half-life of 2.2 hr in a male dog and 3.2 hr a female dog. Perillic acid was the major systemic metabolite in the dogs, accounting for 95% of the combined area under the plasma profiles of perillic acid and dihydroperillic acid. The appearance of the plasma profile of dihydroperillic acid suggested that it was not a direct metabolite of perillyl alcohol, but rather, a product of additional biotransformation of perillic acid. In a group of dogs treated according to a multiple dosing regimen, in which 20-400 mg/kg doses were given ig every 8 hr for 14 days, plasma concentrations of both metabolites tended to increase with escalations in the dose and there was no discernable difference between their concentrations in male and female dogs. In a similar study conducted in male rats, plasma levels of perillic acid were relatively invariant on days 1 through 14 in each animal, indicating that there was probably no accumulation. The geometric mean concentration of perillic acid increased from 40 +/- 18 micro M to 386 +/- 170 micro M as the dose was escalated from 25 to 300 mg/kg. The concentration of dihydroperillic acid was relatively constant during days 4-14 and very similar to that of perillic acid. The plasma concentrations of the two metabolites observed at the upper dose levels were similar to those reported by Gould in rats treated with the optimal therapeutic dose of dietary perillyl alcohol.